This section is intended to introduce the reader to various aspects of art that may be related to various aspects of the present invention, which are described and/or claimed below. This discussion is believed to be helpful in providing the reader with background information to facilitate a better understanding of various aspects of the present invention. Accordingly, it should be understood that these statements are to be read in this light, and not as admissions of prior art.
The inhibition or activation of biological processes with drugs that act as antagonists or agonists is the basis of the chemotherapy of diseases. For a small molecule to interact with high affinity and specificity with a given protein target requires that the molecule is able to establish a sufficient number of molecular interactions which will provide the required free energy of binding. If the active site of a protein is a deep pocket, small molecule drugs can take advantage of interactions that can be established on all sides of the molecule. However, if the active site of a protein target is relatively flat, the contacts a small molecule can establish may be limited to one face. As a result, the affinity of the small molecule for the target may not be very high.
Protein-protein interactions (PPIs) occur when two or more proteins bind together, and they represent a large group of drug targets. However, PPIs are difficult to disrupt because they usually involve large, two-dimensional (i.e., flat) target surfaces. The interface of protein-protein interactions can be rather large and may involve contacts between 20 or 30 amino acids on both proteins. Conventional small molecule drugs can bind with high affinity in deep protein pockets that provide a three-dimensional building space. However, due to the flat surface of many PPI's, small molecules often cannot establish the number of contacts required for a high affinity binding event that can compete with the binding of the large protein ligand to the target. Thus, most PPIs are “undruggable” with traditional small molecules, which is a problem.
The development of small molecules that can inhibit PPIs could have great benefit. For example, K-Ras is a member of the small GTP binding protein family which constitutes over 100 members10. Wild-type K-Ras oscillates between an active, GTP-bound form and an inactive GDP form11,12. The GTP-bound form has a distinct conformation that promotes its interaction with multiple effector proteins via its Switch I and Switch II regions. 30% of all solid tumors show activating point mutations in K-Ras. K-Ras mutants are insensitive to down regulation by GAP-mediated hydrolysis of bound GTP. As a result, mutant K-Ras is “frozen” in its activated form which results in constitutive signaling into proliferation and survival pathways. K-Ras point mutations are usually found at codons 12, 13 and 61 and less frequently at codons 59 and 63. Typical point mutations at codon 12 replace a glycine by aspartate or valine. Transgenic mouse models have demonstrated that expression of mutated K-Ras by itself13 or in combination with the introduction of other oncogenic lesions14,15 can promote cancer. Similarly, it was shown that cancer cells undergo apoptosis if oncogenic K-Ras is down regulated by RNA interference.16 These data strongly suggest that inhibition of oncogenic K-Ras may have therapeutic benefits in cancer patients. K-Ras is farnesylated and located at the inner leaflet of the plasma membrane. In recent years the pharmaceutical industry has attempted to target oncogenic K-Ras proteins by disrupting its subcellular localization with farnesyl transferase inhibitors (FTIs). However, in clinical trials FTIs have proved largely ineffective in pancreatic and other cancers, possibly because the loss of FT activity is compensated for by geranyl-geranyl transferase17.
In view of the above issues, there have been previous attempts develop approaches to modulate the biological activity of small molecules. For example, prior studies have demonstrated that the affinity of a linear peptide for the Fyn SH2 domain can be enhanced when the peptide is coupled to an FKBP ligand and bound to FKBP.47 
As another example, it has been shown that conjugation of an FKBP ligand to Congo Red, a dye molecule that binds to beta-amyloid peptide, improved the ability of the dye molecule to disrupt amyloid plaque formation.48 Presumably, binding of FKBP to the molecule creates a steric block FKBP that hinders the beta-amyloid peptide aggregation.
As yet another example, it has been shown that linking a HIV protease inhibitor to an FKBP ligand increased the half-life of the drug in mice.49 It was thought that the association of the bifunctional molecule with FKBP in mammalian cells may have slowed the molecule's metabolism and excretion.
However, a drawback to these previous studies is that they all required a pre-existing ligand with high affinity and specificity to the target of interest. Unfortunately, for many high-value targets such as the flat surfaces involved in protein-protein interactions, no such ligand is available (or possible).
As such, the development of a technique that would allow the disruption of protein-protein interactions, particularly through use of a small molecule therapeutic agent, and particularly without requiring a pre-existing ligand with high affinity and specificity to the target, would be desirable. This need and other needs are satisfied by the present invention.